EP1910330A1 - Heterocyclylamide-substituted thiazoles, pyrroles and thiophenes - Google Patents

Abstract

The invention relates to heterocyclylamide-substituted thiazoles, pyrroles and thiophenes and to processes for preparing them, to their use for the treatment and/or prophylaxis of diseases, and to their use for the production of medicaments for the treatment and/or prophylaxis of diseases, particularly for use as antiviral agents, especially against cytomegaloviruses.

Description

 Heterocycliclamide-substituted thiazoles, pyrroles and thiophenes

The invention relates to heterocyclylamide-substituted thiazoles, pyrroles and thiophenes and processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular for use as antiviral agents, especially against cytomegaloviruses.

WO 99/23091 describes aromatic heterocyclic compounds as antiinflammatory agents, which may, inter alia, also be suitable for the treatment of viral infections, and WO 04/052852 describes 3-pyrrolyl urea derivatives as antiviral agents which carry a carbocycle as a substituent on the urea.

Although structurally different antiviral agents are present on the market, currently available therapies with ganciclovir, valganciclovir, foscarnet and cidofovir are associated with severe side effects, e.g. Nephrotoxicity, neutropenia or thrombocytopenia. In addition, resistance can develop regularly. New means for effective therapy are therefore desirable.

An object of the present invention is therefore to provide new compounds having the same or improved antiviral activity for the treatment of viral infectious diseases in humans and animals.

Surprisingly, it has been found that the substituted heterocycles described in the present invention are highly effective antivirally.

The present invention relates to compounds of the formula

in which

R ^{1 is} a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

R ^{3 is} phenyl or 5- or 6-membered heteroaryl,

in which phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl,

Amino, C ₁ -C ₆ -alkylamino, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,

R ^{4 is} phenyl or 5- or 6-membered heteroaryl,

wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl,

Difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoro- methylthio, C _r C ₆ alkyl, Ci-C ₆ alkoxy, hydroxycarbonyl, Ci-Cβ-alkoxycarbonyl, amino, Ci-C ₆ -alkylamino, aminocarbonyl, and Ci-Cβ-alkylaminocarbonyl .

and

R ⁵ and R ⁶ independently of one another represent hydrogen, methyl or ethyl,

stands for phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, Ci-C ₆ alkyl and QC _6- alkoxy, for a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the nitrogen atom of the urea,

R ^{7 is} C ₁ -C ₆ -alkyl,

where alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₀ aryl and 5- or 6-membered heteroaryl,

in which cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, Trifluoromethylthio, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -

Alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, amino, C 1 -C ₆ -alkylamino, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,

and

R ⁸ and R ⁹ independently of one another represent hydrogen, halogen or C ₁ -C ₆ -alkyl,

where alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₀ aryl and 5- or 6-membered heteroaryl, - -

in which cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, Trifluoromethylthio, C ₁ -C ₆ -alkyl, QC ₆ -

Alkoxy, hydroxycarbonyl, Ci-C ₆ alkoxycarbonyl, amino, QC ₆ - alkylamino, aminocarbonyl and Ci-C ₆ alkylaminocarbonyl,

and their salts, their solvates, and the solvates of their salts.

Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates of the salts; the compounds of the formula (I) mentioned below of the formulas and their salts, solvates and solvates of the salts and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the of formula (I), compounds mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

Alkyl per se and "alk" and "alkyl" in alkoxy. Alkylamino, alkoxycarbonyl and alkyl amino carbonyl stand for a linear or branched alkyl radical having generally 1 to 6 (,, Ci-C ₆ - alkyl "), preferably 1 to 4, more preferably 1 to 3 carbon atoms, for example and preferably methyl , Ethyl, n-propyl, isopropyl, tert -butyl, n -pentyl and n -hexyl.

Alkoxy is, by way of example and by way of preference, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N Dimethylamino, N, N-

Diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino,

Nt-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino. C _r C ₃ -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent. - -

Alkoxycarbonyl is, by way of example and by way of preference, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N Dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl

N-n-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl. Ci-Ca-alkylaminocarbonyl is for example a

Monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or for a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.

Aryl is a mono- or bicyclic aromatic, carbocyclic radical of usually 6 to 10 carbon atoms; by way of example and preferably phenyl and Νaphthyl.

5- or 6-membered heteroaryl is in the context of the invention in general an aromatic, monocyclic radical having 5 or 6 ring atoms and up to 4 heteroatoms from the series S, O and / or Ν. The heteroaryl radical may be bonded via a carbon or heteroatom. Examples which may be mentioned are: thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl.

Cycloalkyl represents a cycloalkyl group having usually 3 to 6 carbon atoms, by way of example and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Halogen is fluorine, chlorine, bromine and iodine.

Preferred in the context of the present invention are compounds of the formula (I)

in which

R ^{1 is} a group of the formula

stands, in which

* represents the point of attachment to the carbonyl group,

R ^{3 is} phenyl or 5- or 6-membered heteroaryl,

wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from

A group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ - Alkoxycarbonyl, amino, C ₁ -C ₆ -alkylamino, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,

R ^{2 is} phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C _r C ₆ alkyl and Ci-C _6- alkoxy,

A is a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the nitrogen atom of the urea,

R ^{7 is} C _r C ₆ -alkyl, where alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₀ aryl and 5- or 6-membered heteroaryl,

in which cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C ₁ -C ₆ -alkyl, QC ₆ - alkoxy, hydroxycarbonyl, Ci-C ₆ alkoxycarbonyl, amino, Ci-C ₆ alkyl amino, aminocarbonyl, and Ci-C ₆ alkylaminocarbonyl,

and

R ⁸ and R ⁹ independently of one another represent hydrogen, halogen or C ₁ -C ₆ -alkyl,

and their salts, their solvates, and the solvates of their salts.

Also preferred in the context of the present invention are compounds of the formula (T)

in which

R ^{1 is} a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

R ^{3 is} phenyl or pyridyl,

wherein phenyl and pyridyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, Ci-C ₄ alkyl and C 1 -C ₄ -alkoxy,

R ^{2 is} phenyl, wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of fluorine, chlorine, trifluoromethoxy, difluoromethoxy, trifluoromethylthio and methyl,

A is a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the nitrogen atom of the urea,

R ^{7 is} methyl, ethyl or n-butyl,

wherein methyl, ethyl and n-butyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyclopropyl and phenyl,

in which phenyl may be substituted by a substituent trifluoromethyl,

and

R ⁸ and R ⁹ independently of one another represent hydrogen, bromine, chlorine, methyl or ethyl,

and their salts, their solvates, and the solvates of their salts.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{1 is} a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group, and

R ^{3 is} phenyl or pyridyl,

wherein phenyl and pyridyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, Ci-C ₄ alkyl and QC ₄ -alkoxy.

Also preferred in the context of the present invention are compounds of the formula (I) in which R ^{2 is} phenyl, where phenyl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of fluorine, chlorine , Trifluoromethoxy, difluoromethoxy, trifluoromethylthio and methyl.

Also preferred in the context of the present invention are compounds of the formula (I) in which A represents a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the nitrogen atom of the urea, R ^{7 is} methyl, ethyl or n-butyl,

wherein methyl, ethyl and n-butyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyclopropyl and phenyl,

in which phenyl may be substituted by a substituent trifluoromethyl,

R ^{8 is} hydrogen, bromine, chlorine or methyl,

and

R ^{9 is} hydrogen.

The invention further provides a process for the preparation of the compounds of the formula (I), wherein

according to method [A] compounds of the formula

in which

R ^{1 has} the meaning given above,

in the first stage with a reducing agent and in the second stage in the presence of a carbonic acid derivative with compounds of the formula

H ₂ NR ² (IH),

in which

R ^{2 has} the meaning given above,

or

according to process [B] compounds of formula (H) in the first stage with a reducing agent

and in the second step with compounds of the formula OCN-R ² (IV),

in which

R ^{2 has} the meaning given above,

or

according to method [C] compounds of the formula

in which

R ^{2 has} the meaning given above, and

R ^{10 is} methyl or ethyl,

in the first stage with a base and in the second stage with compounds of the formula

R'-H (VI),

in which

R ^{1 has} the meaning given above,

be reacted in the presence of dehydrating reagents.

The compounds of formulas (HI), (IV) and (VI) are known or can be synthesized by known methods from the corresponding starting materials.

For methods [A] and [B] 1st stage, the following applies:

The reaction is generally carried out in inert solvents, preferably in a temperature range from 0 ^° C. to the reflux of the solvents under atmospheric pressure to 3 bar.

Reducing agents are, for example, palladium on activated carbon and hydrogen, formic acid / triethylamine / palladium on activated carbon, zinc, zinc / hydrochloric acid, iron, iron / hydrochloric acid, iron (II) sulfate / hydrochloric acid, sodium sulfide, sodium disulfide, sodium dithionite, ammonium polysulfide, Sodium borohydride / nickel chloride, tin dichloride, titanium trichloride or Raney nickel and aqueous hydrazine solution, preferably Raney nickel and aqueous hydrazine solution, palladium on activated carbon and hydrogen or formic acid / triethylamine / palladium on activated carbon.

Inert solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert .-Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, in the case of water-miscible solvents, mixtures thereof with water, as the solvent is preferably methanol, ethanol, iso -Propanol or in the case of Raney nickel and aqueous hydrazine solution tetrahydrofuran.

For method [A] 2nd stage:

The reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to 40 ° C at atmospheric pressure.

Carbonic acid derivatives are, for example, N, N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, phenyl chloroformate or 4-nitrophenyl chloroformate, preferably N, N-carbonyldiimidazole.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether , Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, in the case of water-miscible solvents, mixtures thereof with water, is preferred dimethyl sulfoxide.

For method [B] 2nd stage:

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to reflux of the solvents under atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or Trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide , Dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, preferably tetrahydrofuran or methylene chloride.

Examples of bases are alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or potassium tert-butoxide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferably triethylamine.

For method [C] 1st stage, the following applies:

The reaction is generally carried out in inert solvents, preferably in a temperature range from ⁰ ° C. to the reflux of the solvents under normal pressure.

Examples of bases are alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, preferably sodium hydroxide.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of solvents with water, as solvent is preferably a mixture of ethanol and water.

For method [C] 2nd stage:

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -70 ⁰ C to 40 ⁰ C at atmospheric pressure.

Examples of suitable dehydrating reagents include carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyl-oxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2 dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ' , N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -l, l, 3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazole -l-yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (HATU) or 1-hydroxybenzotriazole (HOBt) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures from these, with bases.

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine (DMAP) or diisopropylethylamine, or DBU, DBN, pyridine, preferred is triethylamine.

Preferably, the condensation is carried out with TBTU and DMAP.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethylsulfoxide, acetonitrile or pyridine, in the case of water-miscible solvents, mixtures thereof with water, preferred is dimethylformamide.

In an alternative method, the carboxylic acids obtained from the first stage of the process [C] in the second stage may first be converted with a chlorinating reagent such as thionyl chloride to the carboxylic acid chloride and then with compounds of the formula (VI) in the presence of a base to give compounds of the formula (I) be implemented.

The compounds of formula (E) are known or can be prepared by reacting compounds of the formula

in which

R ¹⁰ has the meaning given above, - 1 -

in the first stage with a base and in the second stage with compounds of formula (VI), in the presence of dehydrating reagents.

The reaction is carried out as described in method [C].

The compounds of formula (VH) are known or can be prepared by combining compounds of formula

in which

R ^{10 has} the abovementioned meaning,

with fuming nitric acid, concentrated nitric acid, nitrating acid or other mixing ratios of sulfuric acid and nitric acid, optionally in acetic anhydride as solvent, preferably in a temperature range from room temperature to 60 ⁰ C at atmospheric pressure, are reacted.

The compounds of the formula (VIII) are known or can be synthesized by known processes from the corresponding starting materials.

The compounds of the formula (V) are known or can be prepared by reacting compounds of the formula (VII) in the first stage with a reducing agent and in the second stage in the presence of a carbonic acid derivative with compounds of the formula (IH) or in the second stage Compounds of formula (IV) are reacted.

The reaction is carried out as described in methods [A] and [B].

Synthetic Scheme 1:

Synthesis Scheme 2:

The compounds of the general formula (I) according to the invention show an unforeseeable, surprising activity spectrum. They show an antiviral activity against representatives of the group of herpes viridae (herpesviruses), especially against cytomegaloviruses (CMV), in particular against the human cytomegalovirus (HCMV). They are thus suitable for the treatment and prophylaxis of diseases, especially infections with viruses, in particular the viruses mentioned above, and the infectious diseases caused thereby. A virus infection is understood below to mean both an infection with a virus and an infection caused by a virus.

The compounds of the general formula (I) can be used because of their special properties for the preparation of medicaments which are suitable for the prophylaxis and / or treatment of diseases, in particular viral infections.

As indication areas can be mentioned for example:

1) Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).

2) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients, who often develop life-threatening HCMV pneumonitis, encephalitis, gastrointestinal and systemic HCMV infections.

3) Treatment and prophylaxis of HCMV infections in newborns and infants.

4) Treatment of acute HCMV infection in pregnant women.

5) Treatment of HCMV infection in immunosuppressed patients in cancer and cancer therapy.

6) Treatment of HCMV-positive cancer patients with the aim of reducing HCMV-mediated tumor progression (see J. Cinatl, et al., FEMS Microbiology Reviews 2004, 28, 59-77).

The compounds according to the invention are preferably used for the preparation of medicaments which are suitable for the prophylaxis and / or treatment of infections with a member of the group of herpes viridae, in particular a cytomegalovirus, in particular the human cytomegalovirus.

Because of their pharmacological properties, the compounds according to the invention can be used alone and, if required, also in combination with other active substances, in particular antiviral agents - -

Agents such as ganciclovir, valganciclovir or acyclovir, for the treatment and / or prevention of viral infections, in particular of HCMV infections used.

The present invention further provides for the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably viral infections, in particular infections with the human cytomegalovirus (HCMV) or another member of the group of herpes viridae.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an antivirally effective amount of the compounds of the invention.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders , Emulsions, suspensions, aerosols or solutions. The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion treatment in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milk, pastes , Foams, scattering powders, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

In general, it has been found to be advantageous to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight to achieve effective results when administered intravenously, and for oral administration the dosage is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg of body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the above upper limit exceeded must become. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

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A. Examples

Used abbreviations:

BINAP 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl

Example. Example

CD ₃ CN Deuteroacetonitrile

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DCM dichloromethane

DIEA N, N-Diisopropylethylamine (Hünig Base)

DMAP 4-N, N-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory

EDCI x HCI Ν '- (3-dimethylaminopropyl) -Ν-ethylcarbodiimide hydrochloride

EE ethyl acetate (ethyl acetate)

EI electron impact ionization (in MS)

ESI electrospray ionization (in MS)

Mp melting point sat. saturated h hour

HATU 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluromum hexafluorophosphate

HBTU O- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

HPLC high pressure, high performance liquid chromatography i. V. concentrated in vacuo. concentrated

LC-MS liquid chromatography-coupled mass spectrometry

LDA lithium diisopropylamide

Literature (position)

Solution. Solution

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy proz. percent RP-HPLC reverse phase HPLC

RT room temperature

R "retention time (by HPLC)

M.p. melting point

TBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

THF tetrahydrofuran diluted dilute aq. aqueous

HPLC and LC-MS methods:

Method 1 (LC-MS): Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l water + 0.5 mL 50% formic acid, eluent B: 1 l acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A - »3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 mL / min, 2.5 min / 3.0 min / 4.5 min 2 mL / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 2 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l water + 0.5 mL 50% formic acid, eluent B: 1 l acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 mL / min, 2.5 min / 3.0 min / 4.5 min 2 mL / min; Oven: 5O ⁰ C; UV detection: 208-400 nm.

Method 3 CLC-MS): Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l water + 0.5 mL 50% formic acid, eluent B: 1 l acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 mL / min, 2.5 min / 3.0 min / 4.5 min 2 mL / min; Oven: 50 ^° C .; UV detection: 210 nm. starting compounds

Example IA

1-methyl-2-trichloroacetyl-1H-pyrrole

1.09 mL (12.3 mmol) of trichloroacetyl chloride are placed under argon in 5 mL DCM and added dropwise a solution of N-methylimidazole in 3 mL DCM at RT within 30 min. The mixture is stirred overnight at RT, the reaction solution is concentrated and the residue is purified on a flash frit (cyclohexane, cyclohexane / ethyl acetate 40: 1). The product is obtained as a liquid.

Yield: 2.12 g (76% of theory)

LC-MS (Method 1): R _t = 2.34 min .; MS (EI ⁺ ): m / z = 225 (M ⁺ )

Example 2A

1-methyl-nitro-trichloroacetyl-1H-pyrrole

2.12 g (9:34 mmol) of l-methyl-2-trichloroacetyl-l H-pyrrole are dissolved in 9.5 ml of acetic anhydride, cooled to -20 ⁰ C and treated with 12:43 mL (9:34 mmol) of nitric acid. The mixture is allowed to warm slowly to RT and stirred for a further 1 h at RT. The reaction mixture is poured onto 95 g of ice and stirred vigorously for 2.5 h (initially oily deposition, then crystallization). The precipitate is filtered off with suction, stirred with 20 ml of methanol, filtered and dried overnight in vacuo. To remove the regioisomer also formed, the mixture is stirred for 2 h with 10 mL of acetic acid / water 1: 1, the solid filtered off and dried in vacuo. A solid is obtained. Yield: 1.71 g (67% of theory)

LC-MS (Method 2): R, = 2.51 min.

¹ H NMR (400MHz, DMSO-U ₆ ): δ = 8.58 (d, IH), 7.80 (d, IH), 4.00 (s, 3H).

Example 3A

1-Methyl-4-nitro-1 H-pyrrole-2-carboxylic acid ethyl ester

0.50 g (1.84 mmol) of 1-methyl-4-nitro-2-trichloroacetyl-1H-pyrrole are placed in 5 mL of ethanol, treated with 0.26 mL (1.84 mmol) of triethylamine and stirred at RT for 2 h. 5 ml of water are added to the reaction mixture, the mixture is stirred at 0 ° C. for 30 minutes and then the precipitate is filtered off with suction and dried in vacuo.

Yield: 321 mg (88% of theory)

LC-MS (Method 3): R, = 2.25 min .; MS (ESf): m / z = 199 (M + H) ⁺

¹ H-NMR (300MHz, DMSO-Cl ₆ ): δ = 8.29 (d, IH), 7.31 (d, IH), 4.27 (q, 2H), 3.92 (s, 3H), 1.30 (t, 3H).

Example 4A

1-Methyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1H-pyrrole-2-carboxylic acid ethyl ester

304 mg (1.53 mmol) of ethyl l-methyl-4-nitro-1H-pyrrole-2-carboxylate are initially charged in 6 ml of ethyl acetate / ethanol (1: 1), with 163 mg (0.15 mmol) of palladium (10% on activated charcoal). and 580 mg (9.20 mmol) of ammonium formate and stirred at 8O ⁰ C for 1 h. After cooling, it is filtered through diatomaceous earth, rinsed with ethanol and the filtrate is freed from the solvent in vacuo. The residue is dissolved in 6 ml of THF, combined with 374 mg (1.84 mmol) of 4-trifluoromethoxyphenyl isocyanate and stirred at RT for 1 h. The reaction solution is concentrated and the residue is purified by RP-HPLC (acetonitrile / water). A solid is obtained.

Yield: 486 mg (85% of theory)

LC-MS (Method 3): R, = 2.61 min .; MS (ESf): m / z = 372 (M + H) ⁺

¹ H-NMR (300MHz, DMSO- (I ₆ ): δ = 8.80 (s, IH), 8.39 (s, IH), 7.53 (m, 2H), 7.26 (d, 2H), 7.20 (d, IH) , 6.72 (d, IH), 4.20 (q, 2H), 3.82 (s, 3H), 1.28 (t, 3H).

Example 5A

l-methyl-4 - [({[4- (trifluoromethoxy) phenyl] ammo} carbonyl) amino] -lH-pyrrole-2-carboxylic acid

470 mg (1.27 mmol) of ethyl 1-methyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1H-pyrrole-2-carboxylate are initially introduced in 5 ml of THF, 152 mg (6.33 mmol) Lithium hydroxide in 1 mL of water and stirred overnight at reflux. The reaction mixture is concentrated, the residue is acidified with 2M hydrochloric acid and the resulting precipitate is filtered off with suction and dried in vacuo. A solid is obtained.

Yield: 429 mg (98% of theory)

LC-MS (Method 2): R ₁ = 2.09 min .; MS (ESI ⁺ ): m / z = 344 (M + H) ⁺

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 12.16 (bs, IH), 9.01 (s, IH), 8.58 (s, IH), 7.53 (m, 2H), 7.25 (d, 2H), 7.18 (d, IH), 6.63 (d, IH), 3.80 (s, 3H). Example 6A

1- (5-methylpyridin-2-yl) piperazine

step 1

1- (tert-butyloxycarbonyl) -4- (5-methylpyridin-2-yl) piperazine

2.50 g (19.6 mmol) of 2-methyl-5-chloropyridine and 4.38 g (23.5 mmol) of N- (tert-butyloxycarbonyl) -piperazine are dissolved in 50 ml of absolute toluene under an argon atmosphere. Is then added 26.2 g (23.5 mmol) of sodium tert-butoxide, 0:37 g (0:59 mmol) of BINAP and 0.36g (0:39 mmol) of tris (dibenzylideneacetone) dipalladium are added and heated for 12 h at 70 ⁰ C. After cooling, the reaction mixture treated with diethyl ether, washed three times with saturated sodium chloride solution, dried over sodium sulfate and freed from the solvent in vacuo. The residue was purified by flash chromatography (cyclohexane / ethyl acetate 9: 1).

Yield: 5.27 g (97% of theory).

LC-MS (Method 1): R _t = 1.26 min .; MS (ESf): m / z = 278 (M + H) ⁺

¹ H-NMR (300MHz, CDCl _3): δ = 8:02 (d, IH), 7:34 (dd, IH), 6:59 (d, IH), 3:55 (m, 4H), 3:45 (m, 4H), 2.21 ( s, 3H), 1.49 (s, 9H).

Level 2

1- (5-methylpyridin-2-yl) piperazine

- -

3.47 g (12.5 mmol) of 1- (tert-butyloxycarbonyl) -4- (5-methylpyridin-2-yl) piperazine are dissolved in 10 ml of dioxane and 31 ml (125 mmol) of hydrogen chloride in dioxane (4 molar) are added. It is allowed to stir for 2 h at RT. It is then concentrated, the residue is basified with 1N sodium hydroxide solution and extracted several times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and dried in vacuo.

Yield: 2.18 g (98% of theory).

LC-MS (Method 3): R, = 0.38 min .; MS (ESf): m / z = 177 (M + H) ⁺

¹ H NMR (300 MHz, CDCl ₃ ): δ = 8.02 (d, IH), 7.32 (dd, IH), 6.59 (d, IH), 3.45 (m, 4H), 3.00 (m, 4H), 2.20 ( s, 3H).

Example 7A

1-Ethyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1 H -pyrrole-2-carboxylic acid

The preparation is analogous to Example 5A.

LC-MS (Method 2): R, = 2.10 min .; MS (ESf): m / z = 358 (M + H) ⁺

Example 8A

1-Butyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1H-pyrrole-2-carboxylic acid

The preparation is analogous to Example 5A. LC-MS (Method 3): R ₄ = 2.47 min .; MS (ESI ⁺ ): m / z = 386 (M + H) ⁺

¹ H NMR (300MHz, DMSO-Cl ₆ ): δ = 8.90 (bs, IH), 8.48 (bs, IH), 7.54 (d, 2H), 7.26 (d, 2H), 7.24 (d, IH), 6.73 (d, IH), 4.21 (t, 2H), 1.62 (quint., 2H), 1.25 (sec., 2H), 0.88 (t, 3H).

Example 9A

1 - (Cyclopropylmethyl) -4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1 H -pyrrole-2-carboxylic acid

The preparation is analogous to Example 5A.

LC-MS (method 2): R _t = 2.33 min .; MS (ESf): m / z = 384 (M + H) ⁺

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 8.86 (bs, IH), 8.45 (bs, IH), 7.55 (m, 2H), 7.23-7.32 (m, 3H), 6.68 (d, IH), 4.11 (d, 2H), 1.21 (m, IH), 0.45 (m, 2H), 0.32 (m, 2H).

Example IQA

4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] thiophene-2-carboxylic acid

The preparation is analogous to Example 4A and 5 A starting from 4-aminothiophene-2-carboxylic acid methyl ester (synthesized according to A. A. Kiryano et al., Tetrahedron Lett. 2001, (42), 8797-8800).

Yield: 72 mg (27% of theory, 2 steps)

LC-MS (Method 2): R, = 2.25 min .; MS (ESf): nVz = 347 (M + H) ^{+ 1} H NMR (400MHz, DMSO-d *): δ = 13.1 (bs, IH), 9.10 (bs, IH), 8.98 (bs, IH), 7.69 (s, IH), 7.53-7.60 (m, 3H ), 7.29 (d, 2H).

Example IIA

2 - [({[4- (Trifluermethoxy) phenyl] amino} carbonyl) amino] -l, 3-thiazole-4-carboxylic acid

The preparation is analogous to Example 4A and 5 A starting from 2-amino-l, 3-thiazol-4-carboxylic acid ethyl ester (commercially available from ACROS).

Yield: 290 mg (61% of theory, 2 stages)

LC-MS (Method 2): R, = 2.05 min .; MS (ESI ⁺ ): m / z = 348 (M + H) ⁺

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.8 (bs, IH), 10.9 (bs, IH), 9.22 (bs, IH), 7.91 (s, IH), 7.60 (d, 2H), 7.32 (d, 2H).

Example 12A

5-methyl-2 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -l, 3-thiazole-4-carboxylic acid

The preparation is carried out analogously to Example 4A and 5 A starting from 2-amino-5-methyl-l, 3-thiazole-4-carboxylic acid methyl ester (commercially available from Tyger Scientific).

Yield: 148 mg (40% of theory, 2 steps)

LC-MS (Method 3): R, = 2.47 min .; MS (ESI ⁺ ): m / z = 362 (M + H) ⁺

¹ H NMR (300MHz, DMSO-Cl ₆ ): δ = 12.7 (bs, IH), 10.7 (bs, IH), 9.18 (bs, IH), 7.59 (d, 2H), 7.32 (d, 2H), 3.34 (s, 3H). Example 13A

5-chloro-2 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -l, 3-thiazole-4-carboxylic acid

The preparation is carried out analogously to Example 4 A and 5 A starting from ethyl 2-amino-5-chloro-1,3-thiazole-4-carboxylate (synthesis described in KJ Hodgetts et al., Org. Lett. 2002, (4) , 1363-1366).

Yield: 365 mg (89% of theory, 2 stages)

LC-MS (Method 3): R, = 2.51 min .; MS (ESf): m / z = 382 (M + H) ⁺

¹ H NMR (300MHz, DMSOd ₆ ): δ = 13.2 (bs, IH), 11.2 (bs, IH), 9.28 (bs, IH), 7.58 (m, 2H), 7.33 (m, 2H).

Example 14A

5-Bromo-2 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1,3-thiazole-4-carboxylic acid

The preparation is carried out analogously to Example 4 A and 5 A starting from 2-amino-5-bromo-l, 3-thiazol-4-carboxylic acid ethyl ester (synthesis described in JF Okonya et al., Tetrahedron Lett., 2002, (43) , 7051-7054).

Yield: 343 mg (74% of theory, 2 stages)

LC-MS (Method 2): R, = 2.22 min .; MS (ESf): m / z = 426 (M + H) ⁺

¹ H NMR (300MHz, DMSOd ₆ ): δ = 13.1 (bs, IH), 11.2 (bs, IH), 9.28 (bs, IH), 7.58 (m, 2H), 7.32 (m, 2H). Example 15A

2 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -1,3-thiazole-5-carboxylic acid

The preparation is carried out analogously to Example 4A and 5A starting from 2-amino-l, 3-thiazol-5-carboxylic acid ethyl ester (commercially available from RareChem).

Yield: 200 mg (55% of theory, 2 stages)

LC-MS (Method 3): R, = 2.36 min .; MS (ESf): m / z = 348 (M + H) ⁺

¹ H NMR (300MHz, DMSOd ₆ ): δ = 12.8 (bs, IH), 10.9 (bs, IH), 9.21 (bs, IH), 7.92 (s, IH), 7.60 (d, 2H), 7.33 ( d, 2H).

embodiments

example 1

N- {1-Methyl-5 - [(4-pyridin-2-yl-piperazin-1-yl) carbonyl] -1 H -pyotolu-3-yl} -N '- [4- (trifluoromethoxy) -phenyl-urea

50 mg (0.15 mmol) of 1-methyl-4 - [({[4- (trifluoromethoxy) phenyl] amino} carbonyl) amino] -H-pyrrole-2-carboxylic acid (Example 5A) are initially charged in 1 ml of DMF and washed with 56 mg (0.18 mmol) of O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) and 8.9 mg (0.07 mmol) of 4- (dimethylamino) -pyridine (DMAP). Subsequently, 29 mg (0.18 mmol) of 1- (2-pyridyl) piperazine are added and the mixture is stirred at RT for 8 h. The reaction solution is purified by RP-HPLC (acetonitrile / water). A solid is obtained.

Yield: 54 mg (76% of theory)

LC-MS (Method 1): R, = 1.61 min., MS (ESf): m / z = 489 (M + H) ⁺

¹ H NMR (300MHz, DMSOd ₆ ): δ = 8.75 (s, IH), 8.32 (s, IH), 8.13 (dd, IH), 7.50-7.59 (m, 3H), 7.25 (d, 2H), 7.02 (d, IH), 6.86 (d, IH), 6.68 (dd, IH), 6.28 (d, IH), 3.72 (m, 4H), 3.64 (s, 3H), 3.55 (m, 4H).

Example 2

N- (1-methyl-5 - {[4- (5-methylpyridin-2-yl) piperazin-1-yl] carbonyl} -1H-pyrrol-3-yl) -N '- [4- (trifluoromethoxy) phenyl ]urea

- -

The preparation is carried out analogously to Example 1 from Example 5A and 6A.

Yield: 50 mg (68% of theory)

LC-MS (Method 1): R ₄ = 1.66 min .; MS (ESf): m / z = 503 (M + H) ⁺

¹ H NMR (300MHz, DMSO-Cl ₆ ): δ = 8.75 (bs, IH), 8.32 (bs, IH), 7.98 (d, IH), 7.53 (m, 2H), 7.42 (dd, IH), 7.25 (d, 2H), 7.02 (d, IH), 6.80 (d, IH), 6.28 (d, IH), 3.68-3.76 (m, 4H), 3.63 (s, 3H), 3.45-3.53 (m, 4H), 2.17 (s, 3H).

Example 3

N- {1-Ethyl-5 - [(4-pyridin-2-yl-piperazin-1-yl) carbonyl] -1-H-pyrrol-3-yl} -N '- [4- (trifluoromethoxy) -phenyl-urea

The preparation is analogous to Example 1 from Example 7A and 6A.

Yield: 29 mg (43% of theory)

LC-MS (Method 2): R, = 1.79 min .; MS (ESf): m / z = 503 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 8.74 (bs, IH), 8.32 (bs, IH), 8.13 (d, IH), 7.49-7.60 (m, 3H), 7.22-7.28 (m , 2H), 7.08 (s, IH), 6.87 (d, IH), 6.68 (dd, IH), 6.26 (s, IH), 4.04 (q, 2H), 3.68-3.77 (m, 4H), 3.50- 3.58 (m, 4H), 1.26 (t, 3H).

Example 4

N- (l-ethyl-5 - {[4- (5-methylpyridin-2-yl) piperazin-l-yl] carbonyl} -lH-pyrrol-3-yl) -N ^l - [4- (trifluoro methoxy ) phenyl] urea

The preparation is analogous to Example 1 from Example 7A and 6A.

Yield: 26 mg (39% of theory)

LC-MS (Method 2): R, = 1.80 min .; MS (ESf): m / z = 517 (M + H) ⁺

¹ H NMR (400MHz, DMSOd ₆ ): δ = 8.75 (bs, IH), 8.32 (bs, IH), 7.98 (m, IH), 7.54 (m, 2H), 7.42 (m, IH), 7.26 ( m, 2H), 7.08 (m, IH), 6.80 (d, IH), 6.25 (s, IH), 4.03 (q, 2H), 3.68-3.76 (m, 4H), 3.44-3.52 (m, 4H) , 2.18 (s, 3H), 1.25 (t, 3H).

Example 5

N- {1-Butyl-5 - [(4-pyridin-2-yl-piperazin-1-yl) carbonyl] -1H-pyrrol-3-yl} -N '- [4- (trifluoromethoxy) -phenyl] -urea

The preparation is carried out analogously to Example 1 from Example 8A.

Yield: 41 mg (69% of theory)

LC-MS (Method 2): R, = 2.11 min .; MS (ESI ⁺ ): m / z = 531 (M + H) ^{+ 1} H NMR (400MHz, DMSO-d "): δ = 8.75 (bs, IH), 8.33 (bs, IH), 8.12 (d, IH), 7.58 (m, IH), 7.54 (d, 2H), 7.26 (d, 2H), 7.07 (d, IH), 6.87 (d, IH), 6.68 (dd, IH), 6.26 (d, IH), 4.02 (t, 2H), 3.72 (m, 4H), 3.53 (m, 4H), 1.59 (quint., 2H), 1.18 (sec., 2H), 0.84 (t, 3H).

Example 6

N- (1-Butyl-5 - {[4- (5-methylpyridin-2-yl) piperazin-1-yl] carbonyl} -1H-py? Ol-3-yl) -N '- [4- (trifluoromethoxy ) phenyl] urea

The preparation is analogous to Example 1 from Example 8A and 6A.

Yield: 19 mg (20% of theory)

LC-MS (Method 2): R, = 1.97 min .; MS (ESf): m / z = 545 (M + H) ⁺

¹ H NMR (300MHz, DMSOd ₆ ): δ = 8.74 (bs, IH), 8.32 (bs, IH), 7.98 (d, IH), 7.53 (d, 2H), 7.41 (dd, IH), 7.25 ( d, 2H), 7.07 (d, IH), 6.80 (d, IH), 6.25 (d, IH), 4.02 (t, 2H), 3.72 (m, 4H), 3.47 (m, 4H), 2.16 (s , 3H), 1.59 (quint., 2H), 1.18 (sec., 2H), 0.83 (t, 3H).

Example 7

N - {1 - (Cyclopropylmethyl) -5 - [(4-pyridin-2-yl-piperazin-1-yl) carbonyl] -1H-pyrrol-3-yl} -N '- [4- (trifluoromethoxy) -phenyl] -urea - -

The preparation is carried out analogously to Example 1 from Example 9A.

Yield: 51 mg (86% of theory)

LC-MS (Method 1): R, = 1.84 min .; MS (ESI ⁺ ): m / z = 529 (M + H) ⁺

¹ H NMR (300MHz, DMSOd ₆ ): δ = 8.75 (bs, IH), 8.33 (bs, IH), 8.13 (dt, IH), 7.51-7.61 (m, 3H), 7.27 (d, 2H), 7.13 (d, IH), 6.88 (d, IH), 6.69 (dd, IH), 6.28 (d, IH), 3.90 (d, 2H), 3.73 (m, 4H), 3.53 (m, 4H), 1.12 (m, IH), 0.45 (m, 2H), 0.28 (m, 2H).

Example 8

N- (1- (Cyclopropylmethyl) -5 - {[4- (5-methylpyridin-2-yl) piperazin-1-yl] carbonyl} -1H-pyrrol-3-yl) - N '- [4- (trifluoromethoxy ) phenyl] urea

The preparation is carried out analogously to Example 1 from Example 9A and 6A.

Yield: 52 mg (85% of theory)

LC-MS (Method 1): R, = 1.86 min .; MS (ESI ⁺ ): m / z = 543 (M + H) ⁺

¹ H NMR (300MHz, DMSOd ₆ ): δ = 8.77 (bs, IH), 8.34 (bs, IH), 7.98 (d, IH), 7.54 (d, 2H), 7.41 (dd, IH), 7.25 ( d, 2H), 7.12 (d, IH), 6.80 (d, IH), 6.27 (d, IH), 3.89 (d, 2H), 3.72 (m, 4H), 3.48 (m, 4H), 2.16 (s , 3H), 1.12 (m, IH), 0.45 (m, 2H), 0.28 (m, 2H). Example 9

N- (5- {[4- (5-Methylpyridin-2-yl) piperazine-1-ylcarbonyl} -3-thienyl) -N '- [4- (trifluoromethoxy) phenyl] urea

The preparation is analogous to Example 1 from Example 10A and 6A.

Yield: 60 mg (63% of theory)

LC-MS (Method 3): R ₁ = 2.05 min .; MS (ESf): m / z = 506 (M + H) ⁺

¹ H-NMR (400MHz, DMSO- (I ₆ ): δ = 9.05 (bs, IH), 8.95 (bs, IH), 7.98 (d, IH), 7.56 (d, 2H), 7.47 (s, IH) , 7.39-7.44 (m, 2H), 7.29 (d, 2H), 6.80 (d, IH), 3.75 (m, 4H), 3.51 (m, 4H), 2.16 (s, 3H).

The following compounds are synthesized analogously to Example 1 from the corresponding starting compounds:

- -

B. Evaluation of physiological activity

The in vitro activity of the compounds according to the invention can be shown in the following assays:

Anti-HCMV (Anti-Human Cytomegalovirus) cytopathogenicity tests

The test compounds are used as 50 millimolar (mM) solutions in dimethylsulfoxide (DMSO). Ganciclovir, foscarnet and cidofovir serve as reference compounds. After the addition of 2 .mu.l each of the 50, 5, 0.5 and 0.05 mM DMSO stock solutions of 98 .mu.l cell culture medium in the series 2 AH in duplicate, 1: 2 dilutions with 50 ul medium to 11 row of 96-well Plate. The wells in rows 1 and 12 each contain 50 μl medium. 150 μl of a suspension of 1 × 10 ⁴ cells (human foreskin fibroblasts [NHDF]) are then pipetted into the wells (row 1 = cell control) or into the rows 2- 12 a mixture of HCMV-infected and noninfected NHDF cells ( MOI = 0.001 - 0.002), ie 1-2 infected cells per 1000 non-infected cells. The series 12 (without substance) serves as a virus control. The final test concentrations are 250 - 0.0005 μM. The plates are incubated for 6 days at 37 ° C./5% CO ₂ , ie until all cells are infected in the virus controls (100% cytopathogenic effect [CPE]). The wells are then fixed and stained by adding a mixture of formalin and Giemsa's dye (30 minutes), with double-distilled water. washed and dried in a drying oven at 5O ⁰ C. Thereafter, the plates are visually evaluated with an overhead microscope (plaque multiplier the company Technomara).

The following data can be determined from the test plates:

CC ₅₀ (NHDF) = maximum substance concentration in μM, in which no visible cytostatic effects on the cells are recognizable in comparison to the untreated cell control;

EC ₅₀ (HCMV) = substance concentration in μM, which inhibits the CPE (cytopathic effect) by 50% compared to the untreated virus control;

SI (selectivity index) = CC ₅₀ (NHDF) / EC ₅₀ (HCMV).

Representative in vitro activity data for the compounds according to the invention are given in Table A: Table A

The suitability of the compounds according to the invention for the treatment of HCMV infections can be demonstrated in the following animal model:

HCMV Xenograft Gelfoam ^® model

Animals:

3-4 week old female immunodeficient mice (16-18 g), Fox Chase SCDD or Fox Chase SCID-NOD or SCID-beige are purchased from commercial breeders (Bomholtgaard, Jackson). The animals are kept in isolators under sterile conditions (including litter and food).

Virus Growing:

Human cytomegalovirus (HCMV) strain Davis is grown in vitro on human embryonic foreskin fibroblasts (NHDF cells). After infection of the NHDF cells with a multiplicity of infection (MOI) of 0.01, the virus-infected cells are harvested 5-7 days later and in the presence of Minimal Essential Medium (MEM), 10% fetal calf serum (FCS) with 10% DMSO at - 40 ⁰ C stored. After serial dilution of the virus-infected cells in increments of ten, the titer is determined on 24-well plates of confluent NHDF cells after vital staining with neutral red or fixation and staining with a formalin-Giemsa mixture (as described above).

Preparation of the sponges. Transplantation. Treatment and evaluation:

lxlxl cm collagen sponges (Gelfoam ^® Fa Peasel & Lorey, order no 407534;. KT Chong et al, Abstracts of 39 * Interscience Conference on Antimicrobial Agents and chemotherapeutic Rapy, 1999, p 439;. Kraemer et PM al., Cancer Research 1983, (43): 4822-4827) are first wetted with phosphate-buffered saline (PBS), the trapped air bubbles removed by degassing and then stored in MEM + 10% FCS. 1 × 10 ⁶ virus-infected NHDF cells (infection with HCMV-Davis MOI = 0.01) are detached 3 hours after infection and added dropwise to a moist sponge in 20 μl MEM, 10% FCS. Optionally, 5 ng / μl basic fibroblast growth factor (bFGF) in 25 μl PBS / 0.1% BSA / 1 mM DTT are applied to the infected sponges after 12-13 hours and incubated for 1 hour. For transplantation, the immuno-deficient mice are anesthetized with avertin or a mixture of azepromazine xylazine and ketamine, the back coat is removed with the help of a dry shaver, the epidermis is opened 1-2 cm, relieved and the wet sponges are transplanted under the dorsal skin. The surgical wound is closed with tissue glue. Twenty-four hours after transplantation, the mice are treated orally for a period of 8 days three times a day (7:00 am and 2:00 pm and 7:00 pm), twice a day (8:00 am and 5:00 pm), or once daily (2:00 pm). The dose is 3 or 10 or 30 or 100 mg / kg body weight, the application volume 10 mL / kg body weight. The formulation of the substances takes place in the form of a 0.5% Tylose suspension optionally with 2% DMSO. 9 days after transplantation and 16 hours after the last administration of the substance, the animals are killed without pain and the sponge removed. The virus-infected cells are released by collagenase digestion (330 U / 1.5 mL) from the sponge and stored in the presence of MEM, 10% fetal calf serum, 10% DMSO at -140 ⁰ C. The evaluation is carried out after serial dilution of the virus-infected cells in steps of ten by titer determination on 24-well plates of confluent NHDF cells after vital staining with neutral red or after fixation and staining with a formalin-Giemsa mixture (as described above). The number of infectious virus particles after substance treatment is compared to the placebo-treated control group.

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules, after drying with the magnesium stearate for 5 min. mixed. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the active ingredient is added to the suspension. While stirring, the addition of water takes place. Until the swelling of the Rhodigels swirling is about 6 h stirred. Intravenously administrable solution;

Composition:

1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injection.

production:

The compound according to the invention is dissolved in the water together with polyethylene glycol 400 while stirring. The solution is sterile filtered (pore diameter 0.22 microns) and filled under aseptic conditions in heat sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

Claims

Patcntansprüche

1. Compound of the formula

in which

R ^{1 is} a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

R ^{3 is} phenyl or 5- or 6-membered heteroaryl,

in which phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, Ci-C ₆ - alkyl, Ci-Ce

Alkoxy, hydroxycarbonyl, Ci-C ₆ alkoxycarbonyl, amino, Ci-C ₆ alkyl amino, aminocarbonyl, and Ci-C _ö alkylaminocarbonyl,

R ^{4 is} phenyl or 5- or 6-membered heteroaryl,

in which phenyl and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, - -

Monofluoromethoxy, trifluoromethylthio, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, amino, C ₁ -C ₆ -alkylamino, aminocarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,

and

R ⁵ and R ⁶ independently of one another represent hydrogen, methyl or ethyl,

R ^{2 is} phenyl,

where phenyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy,

A is a group of the formula

stands,

in which

* stands for the link to the carbonyl group,

# represents the point of attachment to the nitrogen atom of the urea,

R ^{7 is} C 1 -C ⁶ -alkyl,

where alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of C ₃ -C ₆ - cycloalkyl, C ₆ -C ₀ aryl and 5- or 6-membered heteroaryl, in which cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxyl, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, Trifluoromethylthio, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C 1 -C ₆ -alkoxycarbonyl, amino, C ₁ -C ₆ -alkylamino, aminocarbonyl and C ₁ -C ₄ -alkylaminocarbonyl,

and

R ⁸ and R ⁹ are independently hydrogen, halogen or C _r C ₆ alkyl,

where alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of C ₃ -C ₆ - cycloalkyl, C ₆ -C ₀ aryl and 5- or 6-membered heteroaryl,

wherein cycloalkyl, aryl and heteroaryl may be substituted with

1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C _r C ₆ alkyl, C ₁ -C ₆ -alkoxy,

Hydroxycarbonyl, C _r C ₆ alkoxycarbonyl, amino, Ci-C ₆ alkyl amino, aminocarbonyl, and Ci-C _ö alkylaminocarbonyl,

or one of its salts, its solvates or the solvates of its salts.

2. A compound according to claim 1, characterized in that

R ^{1 is} a group of the formula

stands,

in which - -

* represents the point of attachment to the carbonyl group,

R ^{3 is} phenyl or 5- or 6-membered heteroaryl,

in which phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are selected independently of one another from the group consisting of halogen, hydroxyl, oxo,

Nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro- methoxy, monofluoromethoxy, trifluoromethylthio, C _r C ₆ alkyl, Ci-C ₆ - alkoxy, hydroxycarbonyl, Ci-C ₆ alkoxycarbonyl, amino, Ci-C ₆ - alkylamino, Aminocarbonyl and C 1 -C 6 -alkylaminocarbonyl,

R ^{2 is} phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, Ci-C ₆ alkyl and Ci -C ₆ -alkoxy,

A is a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the nitrogen atom of the urea,

R ^{7 is} C-Ce-alkyl, where alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of C ₃ -C ₆ - cycloalkyl, C ₆ -C ₀ aryl and 5- or 6-membered heteroaryl,

wherein cycloalkyl, aryl and heteroaryl may be substituted with ^" 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy , Trifluoromethylthio, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, amino, C ₁ -C ₆ -alkylamino, aminocarbonyl and C ₁ -C -alkylaminocarbonyl,

and

R ⁸ and R ⁹ independently of one another represent hydrogen, halogen or C ₁ -C ₆ -alkyl,

or one of its salts, its solvates or the solvates of its salts.

3. A compound according to claim 1 or 2, characterized in that

R ^{1 is} a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

R ^{3 is} phenyl or pyridyl,

in which phenyl and pyridyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, nitro, cyano,

Trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy mono-, C _r C ₄ alkyl and Ci-C ₄ -alkoxy, - -

R ^{2 is} phenyl,

wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of fluorine, chlorine, trifluoromethoxy, difluoromethoxy, trifluoromethylthio and methyl,

A is a group of the formula

stands,

in which

* represents the point of attachment to the carbonyl group,

# represents the point of attachment to the nitrogen atom of the urea,

R ^{7 is} methyl, ethyl or n-butyl,

wherein methyl, ethyl and n-butyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of cyclopropyl and phenyl,

wherein phenyl may be substituted with a substituent trifluoromethyl,

and

R ⁸ and R ⁹ independently of one another represent hydrogen, bromine, chlorine, methyl or ethyl,

or one of its salts, its solvates or the solvates of its salts.

4. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that

according to method [A] a compound of the formula

in which

R ^{1 has} the meaning given in claim 1,

in the first stage with a reducing agent and in the second stage in the presence of a carbonic acid derivative with a compound of the formula

H ₂ NR ² (HI),

in which

R ^{2 has} the meaning given in claim 1,

or

according to method [B] a compound of formula (H) in the first stage with a reducing agent

and in the second stage with a compound of the formula

OCN-R ² (IV),

in which

R ^{2 has} the meaning given in claim 1,

or

according to method [C] a compound of the formula - -

in which

R ^{2 has} the meaning given in claim 1, and

R ^{10 is} methyl or ethyl,

in the first stage with a base and in the second stage with a compound of

formula

R ¹ -H (VI),

in which

R ^{1 has} the meaning given in claim 1,

is reacted in the presence of dehydrating reagents.

5. A compound according to any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 in combination with at least one inert, non-toxic, pharmaceutically suitable excipient.

7. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of viral infections.

8. Use according to claim 7, characterized in that the viral infection is an infection with the human cytomegalovirus (HCMV) or another member of the group of herpes viridae.

9. Medicament according to claim 6 for the treatment and / or prophylaxis of viral infections.

10. A method for combating viral infections in humans and animals by administering an antivirally effective amount of at least one compound according to one of the Claims 1 to 3, a medicament according to claim 6 or a medicament obtained according to claim 7 or 8.